Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies Cindy.

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Presentation transcript:

Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies Cindy S. Ma, PhD, Natalie Wong, BSc Hons, Geetha Rao, MSc, Danielle T. Avery, BApplSci, James Torpy, MPhil, Thomas Hambridge, BSc Hons, Jacinta Bustamante, MD, PhD, Satoshi Okada, MD, PhD, Jennifer L. Stoddard, BS, Elissa K. Deenick, PhD, Simon J. Pelham, MSc, Kathryn Payne, BSc Hons, Stéphanie Boisson-Dupuis, PhD, Anne Puel, PhD, Masao Kobayashi, MD, PhD, Peter D. Arkwright, FRCPCH, DPhil, Sara Sebnem Kilic, MD, Jamila El Baghdadi, PhD, Shigeaki Nonoyama, MD, PhD, Yoshiyuki Minegishi, MD, PhD, Seyed Alireza Mahdaviani, MD, Davood Mansouri, MD, Aziz Bousfiha, MD, Annaliesse K. Blincoe, BHB, MBChB, Martyn A. French, MB ChB, MD, FRACP, FRCPath, FRCP, Peter Hsu, FRACP, PhD, Dianne E. Campbell, FRACP, PhD, Michael O. Stormon, MBBS, FRACP, Melanie Wong, MBBS, PhD, FRACP, FRCPA, Stephen Adelstein, MBBCh, PhD, FRACP, FRCPA, Joanne M. Smart, MBBS, FRACP, David A. Fulcher, MBBS, PhD, FRACP, FRCPA, Matthew C. Cook, MBBS, PhD, FRACP, FRCPA, Tri Giang Phan, MBBS, PhD, FRACP, FRCPA, Polina Stepensky, MD, Kaan Boztug, MD, Aydan Kansu, MD, Aydan İkincioğullari, MD, Ulrich Baumann, MD, Rita Beier, MD, Tony Roscioli, FRACP, PhD, John B. Ziegler, MD, FRACP, Paul Gray, FRACP, Capucine Picard, MD, PhD, Bodo Grimbacher, MD, Klaus Warnatz, MD, PhD, Steven M. Holland, MD, Jean-Laurent Casanova, MD, PhD, Gulbu Uzel, MD, Stuart G. Tangye, PhD Journal of Allergy and Clinical Immunology Volume 136, Issue 4, Pages 993-1006.e1 (October 2015) DOI: 10.1016/j.jaci.2015.05.036 Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Identification of effector subsets within populations of human memory CD4+ T cells. A-H, Naive and memory CD4+ T cells were sorted from healthy control subjects and stimulated with T-cell activation and expansion (anti-CD2/CD3/CD28) beads. Secretion/expression of the indicated cytokines (Fig 1, A-D; mean ± SEM; n = 25-27) or transcription factors (Fig 1, E-H; mean ± SEM; n = 12-19) were determined after 5 days. I, Resolving blood naive (CD45RA+CXCR5−), non-TFH memory (CD45RA−CXCR5−), and cTFH (CD45RA−CXCR5+) cells from healthy control subjects. J and K, CXCR3 and CCR6 expression on naive and non-TFH memory cells. Fig 1, K, depicts the percentage of TH1 (CXCR3+CCR6−), TH2 (CXCR3−CCR6−), TH17 (CXCR3−CCR6+), and TH1/TH17 (CXCR3+CCR6+) subsets among the non-TFH memory population (n = 55-58). L-S, Secretion/expression of the indicated cytokines (Fig 1, L-O; mean ± SEM; n = 10-15) or transcription factors (Fig 1, P-S; mean ± SEM; n = 7-10) by naive, TH1, TH2, TH17, TH1/TH17, and cTFH cell subsets after 5 days of culture with T-cell activation and expansion beads. Significant differences (1-way ANOVA) between naive and memory CD4+ T cells or subsets are indicated. *P < .05, **P < .01, ***P < .005, and ****P < .001. ns, Not significant. Journal of Allergy and Clinical Immunology 2015 136, 993-1006.e1DOI: (10.1016/j.jaci.2015.05.036) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Delineating subsets of human circulating TFH cells. A and B, cTFH cells were defined as CD45RA−CXCR5+CD4+ T cells. CXCR3+CCR6−, CXCR3−CCR6−, CXCR3−CCR6+, and CXCR3+CCR6+ subsets were then detected (n = 55-58). C-G, Naive, non-TFH memory, total cTFH and CXCR3+CCR6−, CXCR3−CCR6+, CXCR3−CCR6− (DN), and CXCR3+CCR6+ (DP) cTFH cell subsets were sorted from peripheral blood and stimulated with T-cell activation and expansion beads. After 5 days, secretion or expression of the indicated cytokines were determined (n = 5-6). H-J, purified subsets of blood CD4+ T cells were cocultured with allogeneic B cells and T-cell activation and expansion beads. IgM, IgG, and IgA secretion was determined after 7 days. Journal of Allergy and Clinical Immunology 2015 136, 993-1006.e1DOI: (10.1016/j.jaci.2015.05.036) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Defects in cytokine production because of monogenic mutations causing different PIDs. A-D, memory CD4+ T cells were sorted from healthy control subjects or patients with the indicated gene mutations and then stimulated with T-cell activation and expansion beads. Production of IFN-γ (Fig 3, A); IL-4, IL-5, and IL-13 (TH2 cytokines; Fig 3, B); IL-17A, IL-17F, and IL-22 (TH17 cytokines; Fig 3, C); and IL-10 and IL-21 (TFH cytokines; Fig 3, D) was determined after 5 days (means ± SEMs). Control subjects, n = 26-35. Patients with mutations in the following genes: STAT3LOF, n = 6; STAT1GOF, n = 7-9; STAT1LOF, n = 5-7; IL21/R, n = 5; IL10R, n = 2; CD40LG, n = 4; NEMO, n = 5-6; BTK, n = 6; ICOS, n = 4; IL12R, n = 5; IFNGR1/2, n = 6; and TYK2, n = 3. See Table E1 for more detailed results. E and F, proportions of total (Fig 3, E) and class-switched (Fig 3, F) memory B cells in healthy control subjects (n = 37) and patients with gene mutations (STAT3LOF, n = 11-12; STAT1GOF, n = 16; STAT1LOF, n = 7; IL21/R, n = 5; IL10R, n = 3-4; CD40LG, n = 4; NEMO, n = 7-10; ICOS, n = 3; IL12R, n = 8; IFNGR1/2, n = 7-8; and TYK2, n = 4) were determined. Significant differences (1-way ANOVA) between control subjects and patients are indicated. **P < .01, ***P < .005, and ****P < .001. Journal of Allergy and Clinical Immunology 2015 136, 993-1006.e1DOI: (10.1016/j.jaci.2015.05.036) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Effect of monogenic mutations on generation of human cTFH cells. A and B, cTFH cells were identified among the population of non-Treg cells as CD45RA−CXCR5+CD4+ T cells. cTFH cell frequencies in healthy donors (n = 72) and patients with mutations in STAT3 (n = 24), STAT1 (GOF [n = 22] and LOF [n = 7]), IL21R/IL21 (n = 5), IL10R (n = 4), CD40LG (n = 10), NEMO (n = 11), BTK (n = 11), ICOS (n = 6), IL12RB1 (n = 8), IFNGR1/2 (n = 7), or TYK2 (n = 4) were determined. C and D, proportions of CXCR3+CCR6−, CXCR3−CCR6+, CXCR3−CCR6−, or CXCR3+CCR6+ subsets among total cTFH cells (healthy donors, n = 71; STAT3, n = 21, STAT1 GOF, n = 20; STAT1 LOF, n = 7; IL21R/IL21, n = 5; IL10R, n = 3; CD40LG, n = 8; NEMO, n = 7; BTK, n = 5; ICOS, n = 6; IL12RB1, n = 3; IFNGR1/2, n = 6; and TYK2, n = 4). E, Production of IL-17A, IFN-γ, IL-21, and IL-10 by sorted cTFH cells from healthy donors, patients with STAT3LOF mutations, or patients with STAT1GOF mutations (mean ± SEM; n = 3-4). Significant differences (1-way ANOVA) between control subjects and patients are indicated. *P < .05 and ****P < .001. Journal of Allergy and Clinical Immunology 2015 136, 993-1006.e1DOI: (10.1016/j.jaci.2015.05.036) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 IFN-γ suppresses B-cell differentiation in vitro and in vivo. A, Phosphorylation of STAT1 or STAT3 in EBV-transformed lymphoblastoid cell lines from healthy control subjects (red histograms) or patients with IFNGR2 (blue) or STAT1 (green) LOF mutations in response to IFN-γ or IL-21. Gray histogram, Response of unstimulated cells from healthy control subjects. B, cTFH cells from healthy control subjects were cocultured with allogeneic normal, IFN-γ receptor 1– or STAT1-deficient B cells in the absence or presence of exogenous IFN-γ. Immunoglobulin secretion was determined after 7 days. Values represent the mean percentage of immunoglobulin secretion (±SEM) in the presence of IFN-γ relative to its absence (defined as 100%). C and D, serum levels of IgG and IgM in patients with IFNGR1/IFNGR2, IL12RB1, or STAT1LOF mutations. The solid upper and lower lines correspond to normal serum immunoglobulin levels in age-matched control subjects. Journal of Allergy and Clinical Immunology 2015 136, 993-1006.e1DOI: (10.1016/j.jaci.2015.05.036) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Aberrant expression of PD-1 on cTFH cells from patients with STAT3LOF, STAT1GOF, and IL21/RLOF mutations. A and B, PD-1 expression on naive, non-TFH memory, and cTFH cells. Contour and histogram plots in Fig 6, A, represent individual healthy control subjects or patients. The graph in Fig 6, B, depicts average PD-1 expression (mean fluorescent intensity [MFI] ± SEM) for all subjects tested (healthy donors, n = 45; patients with mutations in the following genes: STAT3, n = 15; STAT1 GOF, n = 18; STAT1 LOF, n = 7; IL21R/IL21, n = 5; IL10R, n = 4; CD40LG, n = 3; NEMO, n = 5-6; BTK, n = 5-6; ICOS, n = 5; IL12RB1, n = 4; IFNGR1/2, n = 4; and TYK2, n = 4). C and D, PD-1 expression on CXCR3+CCR6−, CXCR3−CCR6+, CXCR3−CCR6−, and CXCR3+CCR6+ cTFH cell subsets cells from healthy control subjects (n = 25) or patients with STAT3LOF (n = 10), STAT1GOF (n = 10), or IL21/RLOF mutations (n = 5). Significant differences (1-way ANOVA) between control subjects and patients are indicated. *P < .05, **P < .01, ***P < .005, and ****P < .001. Journal of Allergy and Clinical Immunology 2015 136, 993-1006.e1DOI: (10.1016/j.jaci.2015.05.036) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions